BACKGROUND AND AIMS:PredictSURE IBD is a prognostic blood test that classifies newly diagnosed, treatment-naïve Inflammatory Bowel Disease (IBD) patients into 'IBDhi' (high-risk) or 'IBDlo' (low-risk) groups (risk of future aggressive disease). We evaluated this assay in a multinational cohort and explored the effect of concomitant corticosteroids on its discrimination. METHODS:One hundred thirty-six (71 Ulcerative colitis [UC], 65 Crohn's Disease [CD]) and 41 (15 UC, 26 CD) patients with active IBD were 'unexposed' and 'exposed', respectively, to corticosteroids at baseline blood sampling. The number of treatment escalations, time to first escalation, and need for repeated escalations were compared between the biomarker subgroups. Another 20 patients (13 UC, 7 CD) were longitudinally sampled over 6 weeks after commencing corticosteroids. RESULTS:In corticosteroids-naïve UC and CD patients, all bowel surgeries (n = 6) and multiple therapy escalations (n = 10) occurred in IBDhi patients. IBDhi UC patients required significantly more treatment escalations, had a shorter time to first escalation, and a greater need for multiple escalations than IBDlo patients. No statistically significant differences were observed among CD patients. In corticosteroid-exposed patients, 66.6% of 'misclassifications' were IBDlo patients who required escalations. Among corticosteroid-treated patients with longitudinal sampling, 81.3% of those classified as IBDhi before steroids switched to IBDlo during therapy. CONCLUSIONS:No significant differences in treatment escalations were observed between biomarker-defined subgroups in CD. However, IBDhi UC patients required significantly earlier and more frequent therapy escalations, highlighting the need to further investigate PredictSURE IBD in UC. Notably, the discrimination ability of the biomarker was unreliable in patients receiving corticosteroid therapy.

Abstract Background Little is known about the relative efficacy of available COVID-19 vaccine types around the world in immune-compromised patients with inflammatory bowel disease (IBD).1,2 We aimed to compare antibody responses to SARS-CoV-2 in patients with IBD who had received mRNA, vector, and inactivated virus vaccines and the impact of medications thereof among multinational sites. Methods Serum samples taken after 1st, 2nd, and 3rd doses of COVID-19 vaccines from patients with IBD seen at 13 sites across Europe, Asia, and North America were prospectively collected between January 2021 and November 2022. We measured anti-Spike (S) and anti-nucleocapsid (N) antibody levels. To identify determinants of serological responses to vaccination, both univariate and multivariate analyses were conducted. Results There were a total of 2,268 patients, including 1,279 Crohn’s disease (CD) and 868 ulcerative colitis (UC) (Table 1). 1552 patients had an mRNA vaccine, 590 an adenovirus vaccine, and 98 an inactivated virus vaccine. At 14-84 days, 85-168 days, and 169+ days after completing a full vaccination series, the proportion of patients who were positive for anti-S antibodies were 98% (n=922/939), 96% (n=700/731), and 98% (n=677/692) for mRNA, 95% (n=378/396), 89% (n=55/62), and 97% (n=33/34) for adenovirus, and 72% (n=21/29), 84% (n=31/37), and 95% (n=55/58) for inactivated virus vaccine, respectively. On univariate analysis, rates of serological response were highest in those who received mRNA vaccines at all six time periods (Figure 1a). Adenovirus vaccine response rates closely resembled the rate of seropositivity in mRNA vaccinated patients. In contrast, inactivated vaccines had a significantly lower percent of patients reaching seropositivity until 169 days or more after the second vaccine dose (p<0.001). Anti-TNF monotherapy and immunomodulator monotherapy were associated with the ability to obtain maximum antibody titres. However, this difference is ablated after the 3rd dose (Figure 1c). Univariate analysis also implicated geographical site, male sex, and a diagnosis of ulcerative colitis as determinants of serological responses. On multi-variable analysis, vaccine type (p < 0.001 at every time point analysed) and the use of immunomodulators (p <0.001 at time points 1 and 3) were confirmed as independent determinants of vaccine responsiveness across the study populations. Conclusion Our data suggests that while there is variability between geographical centers, the response rates are high worldwide, and the key determinants of serological response to vaccines are the use of immunosuppressive agents and vaccine class.3 These data are important considerations for better pandemic preparedness in the IBD community worldwide. References (1)Wong SY, Wellens J, Helmus D, et al. Geography Influences Susceptibility to SARS-CoV-2 Serological Response in Patients With Inflammatory Bowel Disease: Multinational Analysis From the ICARUS-IBD Consortium. Inflamm Bowel Dis. 2023;29(11):1693-1705. doi:10.1093/ibd/izad097 (2)Goodyear CS, Patel A, Barnes E, et al. Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Rheumatol. 2024;6(6):e339-e351. doi:10.1016/S2665-9913(24)00065-1 (3)Barnes E, Goodyear CS, Willicombe M, et al. SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease. Nat Med. 2023;29(7):1760-1774. doi:10.1038/s41591-023-02414-4

BACKGROUND & AIMS:The efficacy and safety of extended treatment with risankizumab (RZB), an anti-interleukin-23 p19 monoclonal antibody, were evaluated in patients with moderate to severe Crohn's disease (CD) who did not achieve clinical response to 12 weeks (W) RZB induction treatment ('initial nonresponders'). METHODS:Initial nonresponders to intravenous (IV) RZB induction (600 mg or 1200 mg at W0, W4, and W8) were rerandomized 1:1:1 to receive extended blinded RZB treatment (1200 mg IV at W12, W16, and W20, or subcutaneous [SC] 180 mg or 360 mg at W12 and W20). Patients with clinical response to SC RZB at W24 ('delayed responders') continued their dose in FORTIFY. Clinical, endoscopic, and safety outcomes were evaluated. RESULTS:Most initial nonresponders achieved stool frequency (SF)/ abdominal pain score (APS) clinical response by W24 (76.2% [180 mg SC], 63.7% [360 mg SC], 62.3% [1200 mg IV]), whereas a subset also achieved W24 SF/APS clinical remission (43.0%, 45.1%, and 22.1%), endoscopic response (32.4%, 32.5%, and 40.5%), and endoscopic remission (25.1%, 18.0%, and 23.5%). Most delayed responders to SC RZB continued to demonstrate clinical response at FORTIFY W52 (56.7% [180 mg SC], 69.7% [360 mg SC]), along with SF/APS clinical remission (43.3% and 54.5%), endoscopic response (36.7% and 45.5%), and endoscopic remission (40.0% and 42.4%). Numerically greater efficacy was generally observed with 360 mg SC vs 180 mg SC. The safety profile of extended treatment was consistent with previously reported trials. CONCLUSIONS:Most initial nonresponders to IV RZB induction who received 12W of extended RZB treatment demonstrated improved clinical and endoscopic outcomes at W24. Improvements in patients who received SC RZB extended treatment were maintained during FORTIFY. Extended treatment was well tolerated with no new safety risks identified. CLINICALTRIALS:gov: MOTIVATE (Number: NCT03104413), ADVANCE (Number: NCT03105128), and FORTIFY (Number: NCT03105102).

Abstract Background The FORTIFY maintenance open-label extension (OLE) is an ongoing phase 3 substudy evaluating the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, in patients (pts) with moderate to severe Crohn’s disease (CD). Previously, we presented the 2-year (Y) results from the OLE assessed through MAR2023, at which time most pts had yet to complete the week (W) 152 visit. Here, we report the full 2Y results with all pts having completed the W152 study visit. Methods Pts completing 52W of RZB maintenance were eligible to enroll in the FORTIFY (NCT03105102) OLE1,2, during which pts received 180mg subcutaneous (SC) RZB every 8W (Q8W), starting at W56, except pts who previously received rescue therapy (details in Figure footnote) as they continued 360mg SC Q8W in the OLE. Pts with inadequate response (increased symptoms + objective marker of inflammation) during the OLE received rescue therapy and remained on 360mg SC through the end of the study. Efficacy (endpoint definitions in Figure footnote) was assessed through W152 of RZB treatment (2Y in the OLE) using as observed (AO) and nonresponder imputation (NRI) methods. Data before receiving rescue therapy and upon/after receiving rescue therapy in the OLE are presented separately. All enrolled pts were included in the safety analysis. Treatment-emergent adverse events (TEAEs) reported on/after the first dose in the OLE were summarized (cutoff date: 01MAR2024). Results In the OLE, 1148 pts received ≥1 dose of RZB. Prior to receiving rescue therapy (pt numbers in Figure footnote), efficacy rates (per AO data) remained stable from W56 to W152 (both doses) for stool frequency/abdominal pain score (SF/APS) clinical remission (180mg, 69.8% to 74.8%; 360mg, 46.6% to 61.8% (84/136) and per CD Activity Index (CDAI) clinical remission (180mg, 72.9% to 81.1%; 360mg, 54.5% to 72.0%, endoscopic response (180mg: 57.5% to 75.7%; 360mg: 40.7% to 66.0%), and endoscopic remission (180mg: 41.6% to 62.4%; 360mg: 24.7% to 43.8%) (Figure). Similar results were observed per NRI data. Pts who received rescue therapy in the OLE (180mg, n=147; 360mg, n=76) also demonstrated clinical and endoscopic improvements by W152, irrespective of RZB dose received prior to rescue. The profiles of TEAEs and AEs of special interest were consistent with RZB’s known safety profile (Table).3,4 Conclusion Durable clinical and endoscopic efficacy was observed with long-term RZB maintenance therapy in the FORTIFY OLE. Pts who received rescue therapy in the OLE also showed clinical and endoscopic improvements by W152. No new safety risks for RZB were identified, supporting its long-term use in treating CD. References 1. Ferrante M, Feagan BG, Panés J, Baert F, Louis E, Dewit O, et al. Long-Term Safety and Efficacy of Risankizumab Treatment in Patients with Crohn’s Disease: Results from the Phase 2 Open-Label Extension Study. Journal of Crohn’s and Colitis. 2021 Jun 2;jjab093. 2. Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. The Lancet. 2022 May;399(10340):2031–46. 3. Papp KA, Blauvelt A, Puig L, Ohtsuki M, Beissert S, Gooderham M, et al. Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up. Journal of the American Academy of Dermatology. 2023 Dec;89(6):1149–58. 4. Ferrante M, Panaccione R, Colombel JF, Dubinsky M, Hisamatsu T, Lindsay JO, et al. DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn’s Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension. Journal of Crohn’s and Colitis. 2024 Jan 24;18(Supplement_1):i168–70.

There is emerging interest in adaptive platform trials for inflammatory bowel disease. In this Comment, we present the results of a workshop that was convened to consider the opportunities and challenges of developing a platform trial in Crohn’s disease.

Abstract Background Part 2 of the ongoing SEQUENCE study examines the long-term efficacy and safety of risankizumab (RZB), an interleukin-23 p19 inhibitor, in patients (pts) with moderate to severe Crohn’s disease (CD). Here, we report the 1-year results from part 2 of the SEQUENCE study. Methods In part 2 of SEQUENCE (NCT04524611), pts randomized to the RZB arm who completed the week (wk) 48 visit could continue to receive open-label 360mg subcutaneous (SC) RZB maintenance dose every 8 wks (Q8w).1 Pts with inadequate response (increased symptoms plus objective marker of inflammation) during part 2 could receive rescue therapy (1 x 600 mg intravenous RZB, then 360 mg RZB SC Q8w). Clinical remission (per CD activity index [CDAI] and per stool frequency [SF]/abdominal pain score [APS]), steroid-free clinical remission, Inflammatory Bowel Disease Questionnaire [IBDQ] response, and IBDQ remission (endpoints defined in Figure footnote) were assessed at wks 56 (baseline of OLE), 80, and 104. Data were assessed for all intent-to-treat pts using as observed (AO) regardless of rescue therapy. Data were also assessed per nonresponder imputation (NRI), where patients were categorised as nonresponders for visits with missing assessments, visits after premature discontinuation of study, and visits after initiation of rescue therapy (if applicable). Treatment-emergent adverse events (TEAEs) reported on or after the first dose in part 2 were analysed (cutoff date: July 11, 2024). Results A total of 224 pts entered part 2 of SEQUENCE. Among the intent-to-treat pts, clinical remission rates (per AO data) remained stable from wk56 to wk104 (CDAI: 75.3% [168/223] to 84.4% [141/167]; SF/APS: 71.2% [158/222] to 74.7% [124/166]) (Figure). Most pts who achieved clinical remission were not receiving steroids at the corresponding visits (Figure). Pts also demonstrated sustained and clinically meaningful improvements in IBDQ response (86.7% [157/181]; AO data) and IBDQ remission (65.3% [126/193]; AO data) at wk104 (Figure). Similar results to AO data were observed per NRI data (Figure). Sixteen (7.1%) pts received rescue therapy during part 2, of which 77.8% (7/9) achieved wk104 clinical remission (CDAI and SF/APS) (AO data). The profiles of TEAEs and TEAEs of safety interest were consistent with the known safety profile of RZB, and adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified (Table).2,3 No deaths occurred during the OLE. Conclusion Pts who received 104 wks of continuous RZB therapy in SEQUENCE demonstrated durable clinical efficacy and quality of life benefits. The safety profile is consistent with the known safety profile of RZB and supports long-term RZB treatment. References 1.Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. N Engl J Med. 2024 Jul 18;391(3):213–23. 2.Papp KA, de Vente S, Zeng J, Flack M, Padilla B, Tyring SK. Long-Term Safety and Efficacy of Risankizumab in Patients with Moderate-to-Severe Chronic Plaque Psoriasis: Results from a Phase 2 Open-Label Extension Trial. Dermatol Ther (Heidelb). 2021 Apr;11(2):487–97. 3.Ferrante M, Panaccione R, Colombel JF, Dubinsky M, Hisamatsu T, Lindsay JO, et al. DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn’s Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension. Journal of Crohn’s and Colitis. 2024 Jan 24;18(Supplement_1):i168–70.

Aims:The utility of circulating cytokine concentrations in ulcerative colitis is limited due to poor assay sensitivity. We aimed to examine the relationship of circulating cytokine concentrations, when measured by ultrasensitive detection, to disease activity, response to induction therapy, and physiological stimuli associated with mucosal injurious events. Methods:Plasma was obtained from adult patients with ulcerative colitis in whom disease activity was assessed; before/after induction therapy; and before/after acute psychological stress and cervical transcutaneous vagal nerve/sham stimulation. Cytokines were measured using an ultrasensitive electrochemiluminescence-based multiplex assay. For stress/vagal-stimulation studies, epithelial injury was quantified by plasma concentrations of intestinal-type fatty acid-binding protein. Results:In 12 patients in remission, 15 with mild-moderately active disease and 6 with severe colitis, concentrations of interleukin-17, IL10, interferon-γ, interleukin-8 and interleukin-6, but not tumor necrosis factor-α or interleukin-12p70, significantly reflected disease activity. In five patients in whom clinical remission was achieved with induction therapy, only interleukin-12p70 changed with a median increase of 65 (IQR 42-303)% (p = 0.006), with no consistent changes in the 10 not in remission. Vagal nerve stimulation had no effect on cytokine concentrations, but, following stress, interleukin-12p70 increased by 37 (13-60)% compared with a reduction of 29 (3-55)% following sham stimulation (p = 0.012), an effect that mirrored that of epithelial injury. Conclusion:Multiple cytokines were detected at sub-pg/mL levels and many showed relationships to disease activity in patients with ulcerative colitis. Effects exerted by interventions associated with epithelial injury were consistently detected by changes in interleukin-12p70 concentrations, but not other cytokines. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000168853 and ANZCTR 12620000569909 [Ultrasound studies]; ClinicalTrials.gov identifier: NCT03908073.

Abstract Background Autologous hematopoietic stem cell transplant (HSCT) emerged as a treatment for refractory CD after several clinical studies including a randomized clinical trial (ASTIC).1,2 In CD patients at risk for bowel failure these studies demonstrated an endoscopic response in over 80% of patients with two transplant related deaths. A recent randomized trial using an alternative fludarabine-based conditioning regimen had unexpected safety outcomes with 2 deaths and renal failure secondary to thrombotic microangiopathy.3 Here we report recent long-term clinical and safety outcomes of HSCT for refractory CD using a cyclophosphamide-ATG conditioning regimen from 3 international centers. Methods Data from 100 patients was reviewed from 3 international centers (Barts Health, UK; Hospital Clinic Barcelona, Spain and Mount Sinai, US) for subjects with medically refractory CD that underwent HSCT. We compiled clinical (CDAI) and endoscopic (SES-CD) evaluations at baseline and the last documented follow-up after HSCT for 68 patients that underwent HSCT since the ASTIC trial. We further compiled additional outcomes including new initiation of advanced therapy, IBD-related surgery, need for parental nutrition, hospitalizations and death. Results As of the last follow-up (median 2 years) post-HSCT, 75% of patients had endoscopic improvement (SES CD↓50%) and 53% endoscopic remission (SESCD<4 ulcer sub-score<1) (N = 56)(Figure 1). 65% of patients were in clinical remission. 46% did not require advanced therapy following HSCT and of patients that started an advanced therapy 84% required a single therapy over 120 patient-years of follow-up (Figure 2). After HSCT there were 7 CD-related surgeries of which 2 were ileostomy reversals. No patients progressed to bowel failure and there were no long-term (>100 days post-HSCT) complications related to transplant including hospitalization, renal failure, death or malignancy. Conclusion In this multicenter international study, the majority of patients demonstrated sustained endoscopic and clinical improvement without progression to bowel failure or with long-term transplant related adverse events over 120 patient-years of follow up. These results support HSCT as a therapy for highly refractory CD patients and the need to refer these patients to international centers of expertise to prevent CD-related morbidity and mortality. References 1.Lindsay JO, Allez M, Clark M, et al. Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol. Jun 2017;2(6):399-406. doi:10.1016/S2468-1253(17)30056-0 2.Lopez-Garcia A, Rovira M, Jauregui-Amezaga A, et al. Autologous Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease: Efficacy in a Single-Centre Cohort. Journal of Crohn's & colitis. Apr 13 2017;doi:10.1093/ecco-jcc/jjx054 3.Lindsay JO, Hind D, Swaby L, et al. Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol. Apr 2024;9(4):333-345. doi:10.1016/S2468-1253(23)00460-0

OBJECTIVE:To evaluate real-world patient-reported experience with subcutaneous (SC) risankizumab administered by on-body device (OBD) in patients with Crohn's disease (CD). METHODS:Uncontrolled observational cross-sectional study in five UK units between October 2023 and May 2024. Patients who had received maintenance risankizumab via SC injection of four pre-filled syringes (PFS) self-administered in hospital were switched to OBD self-injection. Self-Injection Assessment Questionnaires (SIAQ) were completed pre- and post-first OBD use. The primary end-point was "Overall, how satisfied are you with your current way of taking your medication (self-injection)?" from post-injection SIAQ. Baseline patient data were collected retrospectively from medical records. RESULTS:The study recruited 50 patients with moderate-to-severe CD, 48 completed the study. Most (81%) were satisfied/very satisfied with self-injection using OBD vs only 54% with PFS. Satisfaction with the OBD was highest with home use (90% vs 65%). Confidence was high with the OBD; numerically higher rates of patients were confident in giving themselves an injection in the right way (83% vs 64%), in a clean and sterile way (90% vs 74%) and safely (85% vs 72%) post-OBD than before using OBD. Self-injection using the OBD was reported as easy by 92% and convenient by 83% of participants. Most participants reported that they would continue to use the OBD (82%) and be confident to self-inject at home (81%). The OBD was well tolerated. CONCLUSION:The OBD provides a safe, easy to use and convenient way to self-administer risankizumab at home using one injection with improved satisfaction and confidence vs self-administration of four PFS in hospital.

Abstract Background Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), has demonstrated the ability to provide rapid symptom relief within the first week of induction treatment in patients with CD.1 As symptomatic remission is critical for patients, this phase 3 post hoc analysis evaluated the impact of UPA on patient-reported outcomes (PROs) of abdominal pain score (APS) and stool frequency (SF) over the full induction and maintenance time periods. Methods Data were pooled from the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies evaluating patients with moderately to severely active CD with an average daily APS ≥ 2 and/or SF ≥ 4 and received UPA 45 mg (UPA45) once daily (QD) or PBO for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg (UPA15) QD, UPA 30 mg (UPA30) QD, or PBO for 52 weeks. APS and SF were recorded in a daily diary and evaluated over time. Results The average daily APS (mean: PBO 1.9, UPA45 1.9) and SF (mean: PBO 5.6, UPA45 5.4), were similar between the treatment groups at induction baseline (BL). Of patients reporting BL APS ≥ 1 (PBO 91.6%, UPA45 92.4%) or BL SF ≥ 2.8 (PBO 85.6%, UPA45 85.2%), higher proportions of patients receiving UPA vs PBO achieved APS = 0 or SF ≤ 1, or complete resolution of symptoms (APS = 0 and SF ≤ 1) at week 12 of induction, as well as at week 52 of maintenance (all P ≤ .001; Figure 1A). During induction, the mean change from BL in APS and SF was improved with UPA45 vs PBO starting at week 2 through to week 12 (all P < .001; Figure 1B-C). Throughout the 52-week maintenance period, a higher proportion of patients receiving UPA15 or UPA30 achieved APS ≤ 1 or SF ≤2.8 vs PBO (Figure 1B-C). Patients treated with UPA30 demonstrated a numerically higher rate of symptomatic response vs UPA15. In patients who met the Crohn's Disease Activity Index (CDAI) criteria per US labeling (CDAI ≥ 220 at induction BL; clinical response [CR-100] at week 12 with UPA45),2 comparable symptom improvements were observed over time compared to the overall study population. Conclusion Patients with moderately to severely active CD demonstrated improvements in APS and SF as early as 2 weeks after UPA induction treatment. A greater proportion of patients achieved PRO-defined remission within 12 weeks of UPA induction treatment compared with PBO, which were sustained through week 52 of UPA maintenance treatment. References: 1. Colombel, J. F. et al. J. Crohn’s Colitis. 2023;17;i102–3 2. AbbVie Inc. RINVOQ® (upadacitinib) [Package Insert]. N. Chicago, Ill.: AbbVie Inc., 2023

BACKGROUND:Clinical trial recruitment for patients with inflammatory bowel disease (IBD) has become more challenging over time. We aimed to develop recommendations for broadening IBD clinical trial eligibility to improve the inclusion of a more representative patient population in a more efficient timeline. METHODS:We applied the RAND/UCLA Appropriateness Method focused on broadening IBD clinical trial eligibility. A literature review was performed for 7 domains, each representing a different area related to trial recruitment. Based on these domains, 32 statements were developed. A questionnaire was sent to IBD specialists to anonymously vote on each statement with regards to its appropriateness and feasibility. After the first round of voting, participants met for a moderated discussion to review all statements. At the end of the discussion a second round of anonymous voting led to the final recommendations. RESULTS:The final round of voting resulted in 26 statements. All were rated as feasible and 25 of 26 rated as appropriate. Recommendations generally are to be more inclusive of complicated disease phenotypes, more liberal around safety criteria, to recognize the importance of non-invasive imaging and biomarkers, to minimize the washout period and to not enforce a minimum or maximum number of prior medications, to allow a recently recorded colonoscopy to count as a baseline study, and to be less restrictive of age. CONCLUSION:Recommendations to broaden clinical trial eligibility were found to be both appropriate and feasible with a high degree of agreement amongst an international group of IBD specialists.

Abstract Background The SEQUENCE study compared the efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate-to-severe Crohn's disease (CD) who previously failed ≥1 anti-tumour necrosis factor (TNF)a therapies. The second primary endpoint of SEQUENCE, week (wk) 48 endoscopic remission, demonstrated superiority of RZB versus (vs) UST.1 Here, additional endoscopic and clinical/endoscopic composite outcomes are reported. Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study. Pts had a baseline (BL) CD Activity Index (CDAI) of 220-450, average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2, and Simple Endoscopic Score for CD (SES-CD) ≥6 (≥4 for isolated ileal disease). Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, wk4 and wk8, then 360mg subcutaneous [SC] maintenance doses every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance treatment starting at wk8) up to wk48. Randomisation was stratified by BL steroid use and number of failed anti-TNFa therapies. A mandatory steroid taper began at wk2. Here, we assessed at wks 24 and 48 endoscopic remission (SES-CD ≤4 and at least a 2-point reduction versus BL and no subscore >1 in any individual variable, as scored by a central reader), mucosal healing (SES-CD ulcerated surface subscore of 0 in pts with SES-CD ulcerated surface subscore ≥1 at BL, as scored by a central reader), and deep remission (endoscopic remission + clinical remission [CDAI<150]); all were prespecified, non-ranked endpoints, except for wk48 endoscopic remission (second primary endpoint). Treatment differences were adjusted for the randomisation stratification factors. Missing data were handled using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. P values were reported as nominal, except for wk48 endoscopic remission. Results With RZB vs UST, a greater proportion of pts achieved endoscopic remission (wk24: 29.4% vs 17.4%, P= 0.001; wk48: 31.8% vs 16.2%, P<0.0001), mucosal healing (wk24: 25.1% vs 14.4%, P<0.01; wk48: 30.2% vs 12.1%, P<0.0001), and the composite endpoint of deep remission (wk24: 22.0% vs 10.2%, P< 0.001; wk48: 22.7% vs 10.9%, P<0.001) at wk24 and wk48 (Figure). The safety profiles of RZB and UST were consistent with published results.1 Conclusion Exploration of endoscopic outcomes demonstrated that pts with moderate-to-severe CD and prior anti-TNFa failure showed greater achievement of endoscopic remission, mucosal healing, and deep remission with RZB compared to UST. 1doi.org/10.1002/ueg2.12474

Background A previous controlled trial of autologous haematopoietic stem -cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune -ablative regimen of reduced intensity versus standard of care in this patient population. Methods This open -label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub -score of >= 2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem -cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony -stimulating factor (G-CSF) 5 mu g/kg) and stem -cell harvest (minimum 2 center dot 0 x 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7 center dot 5 mg/kg in total) and subsequent stem -cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub -score of 0) without surgery or death at week 48, analysed in the intention -totreat population by central reading. This trial is registered with the ISRCTN registry, 17160440. Findings Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48 -week follow-up; in the control group, nine (90%) reached 48 -week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. Interpretation Although HSCT with an immune -ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.

Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4β7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4β7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4β7 also results in CLA expression, generating CLA+α4β7+ "dual tropic" cells, with both gut and skin trafficking potential, that also express high levels of α4β1 integrin. DC generation of CLA+α4β7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4β7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA-α4β7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn's disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4β7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.

Background and Aims: People with inflammatory bowel disease (IBD) often experience pain, fatigue and bowel incontinence and are at an increased risk of anxiety and depression. Our aim was to assess the impact of these symptoms on health-related quality of life (QoL) in IBD. Methods: In the IBD-BOOST survey, over 26,000 people with IBD across the UK were approached; 8486 participant-completed surveys were returned. Participants' QoL was measured using the EQ-5D-5L questionnaire and their QoL was calculated on a scale ranging from 1 (perfect health) to -0.594 (worst health). Item non-response was imputed. Stages of linear regression models assessed the associations of symptoms with QoL controlling for IBD type, socio-demographic characteristics, co-morbidities and, in further analysis, for IBD activity and IBD control. Results: The EQ-5D-5L questionnaire was fully completed by 8093 (95.4%) participants (mean age of 50 years [SD 15]; 49% with Crohn's disease). The mean QoL was 0.76 (SD 0.23). From the three IBD-related symptoms, pain was associated with the largest QoL decrement (-0.159), followed by fatigue (-0.140) and bowel incontinence (-0.048). Co-occurrence of pain and fatigue further reduced QoL. Clear graded associations were observed between symptom severity and QoL decrements (all trend p < 0.001). Depression and anxiety were also associated with significant QoL decrements (-0.102 and -0.110 for moderate-to-severe anxiety and moderately severe depression, respectively). Worse IBD control and higher IBD activity were associated with lower QoL. Conclusions: We report strong associations between symptoms of pain, fatigue, bowel incontinence, anxiety, depression, and their severity and reduced QoL in IBD. These estimates could inform future IBD management interventions.